Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
A method for altering the PK profile of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike in Cmax. The spike in Cmax is reduced by topically administering the PDE-4 inhibitor in combination with one or more phosphate ester surfactants. Reducing the spike in Cmax will reduce gastrointestinal side effects and result in better patient compliance.
1. A method for reducing gastrointestinal side effects of roflumilast relative to an oral roflumilast formulation marketed under the trademark DALIRESP®, comprising topically administering to said patient, a composition comprising (i) roflumilast in an amount of 0.05%-1% w/w and (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate in an amount of 1.0-25% w/w.
2. The method of claim 1 , wherein the patient is suffering from an inflammatory dermatoses.
3. The method of claim 2 , wherein said roflumilast is in an amount of 0.05% w/w.
4. The method of claim 2 , wherein said roflumilast is present in an amount of 0.15% w/w.
5. The method according to claim 2 , wherein said roflumilast is in an amount of 0.3% w/w.
6. The method of claim 2 , wherein said composition is a foam, wherein said roflumilast is present in an amount 0.3% w/w, wherein said phosphate surfactant blend is present in an amount of 1.0%-10% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water.
7. The method of claim 6 , wherein said patient is suffering from atopic dermatitis.
8. The method of claim 6 , wherein said patient is suffering from psoriasis.
9. The method of claim 6 , wherein said patient is suffering from seborrheic dermatitis.
10. The method of claim 2 , wherein said composition is a cream, wherein said roflumilast is present in an amount 0.3% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from psoriasis.
11. The method of claim 10 , wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w.
12. The method of claim 11 , wherein said phosphate surfactant blend is present in an amount of 10% w/w.
13. The method of claim 2 , wherein said composition is a cream, wherein said roflumilast is present in an amount 0.15% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from atopic dermatitis.
14. The method of claim 13 , wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w.
15. The method of claim 14 , wherein said phosphate surfactant blend is present in an amount of 10% w/w.
16. The method of claim 2 , wherein said composition is a cream, wherein said roflumilast is present in an amount 0.05% w/w, wherein said phosphate surfactant blend is present in an amount of 2.5%-20% w/w, wherein said composition further comprises diethylene glycol monoethyl ether and water, wherein said patient is suffering from atopic dermatitis.
17. The method of claim 16 , wherein said phosphate surfactant blend is present in an amount of 5%-15% w/w.
18. The method of claim 17 , wherein said phosphate surfactant blend is present in an amount of 10% w/w.
19. The method of claim 1 , wherein said composition is a cream or a foam.
20. The method of claim 19 , wherein said composition further comprises hexylene glycol in an amount of 0.1-20% w/w.
21. The method of claim 1 , wherein said composition further comprises at least one additional component selected from the group consisting of a solvent, moisturizer, preservative, pH adjusting solution, and skin penetration enhancer.
22. The method of claim 1 , wherein said phosphate ester surfactant blend is in an amount of 10% w/w.
23. The method of claim 1 , wherein said composition further comprises diethylene glycol monoethyl ether and water.
24. The method of claim 23 , wherein said composition comprises diethylene glycol monoethyl ether in an amount of 25% w/w.
25. The method of claim 1 , wherein said patient is suffering from psoriasis, atopic dermatitis or seborrheic dermatitis.
26. The method of claim 25 , wherein said patient is suffering from atopic dermatitis.
27. The method of claim 25 , wherein said patient is suffering from psoriasis.
28. The method of claim 1 , wherein said composition further comprises diethylene glycol monoethyl ether in an amount of 10-40% w/w.
29. A method for reducing gastrointestinal side effects of roflumilast relative to an oral roflumilast formulation marketed under the trademark DALIRESP®, comprising topically administering to said patient a composition comprising (i) roflumilast in an amount of 0.05%-1% w/w and (ii) a phosphate ester surfactant blend comprising cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate in an amount of 1.0-25% w/w, wherein the peak to trough ratio of roflumilast blood plasma concentration is less than 2 after multiple daily administrations, and wherein the patient is suffering from an inflammatory dermatoses.
30. The method of claim 29 , wherein the peak to trough ratio is less than 2 at steady state.
31. The method of claim 29 , wherein the peak to trough ratio is approximately 1 at steady state.
32. The method of claim 29 , wherein said composition is a cream, and said phosphate ester surfactant blend is in an amount of 10% w/w.
33. The method of claim 29 , wherein said composition is a foam, and said phosphate ester surfactant blend is in an amount of 2% w/w.
34. The method of claim 29 , wherein said composition further comprises diethylene glycol monoethyl ether and water.
35. The method of claim 34 , wherein said diethylene glycol monoethyl ether is in an amount of 10-40% w/w.
36. The method of claim 35 , wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w.
37. The method of claim 29 , wherein said patient is suffering from psoriasis, atopic dermatitis or seborrheic dermatitis.
38. A method for reducing gastrointestinal side effects of a topical roflumilast composition, comprising adding a phosphate ester surfactant blend in an amount of 1.0-25% w/w to a composition comprising roflumilast in an amount of 0.05%-1% w/w and a pharmaceutically acceptable solvent, wherein the phosphate ester surfactant blend comprises cetostearyl alcohol, dicetyl phosphate and ceteth-10 phosphate.
39. The method of claim 38 , wherein said composition is a cream, and said phosphate ester surfactant blend is in an amount of 10% w/w.
40. The method of claim 38 , wherein said pharmaceutically acceptable solvent comprises diethylene glycol monoethyl ether.
41. The method of claim 40 , wherein said diethylene glycol monoethyl ether is in an amount of 10-40% w/w.
42. The method of claim 41 , wherein said diethylene glycol monoethyl ether is in an amount of 15-30% w/w.
43. The method of claim 42 , wherein said diethylene glycol monoethyl ether is in an amount of 25% w/w.